Submissions for variant NM_007294.4(BRCA1):c.5557T>A (p.Tyr1853Asn)

dbSNP: rs2050860958

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247281	SCV001420693	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-29	criteria provided, single submitter	clinical testing	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 433738). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr1853 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20378548, 20516115, 23842040, 29176636, 30287823). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This missense change has been observed in individual(s) with an indication of breast and/or ovarian cancer (PMID: 29470806). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1853 of the BRCA1 protein (p.Tyr1853Asn).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001247281	SCV001774696	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5557T>A (p.Tyr1853Asn) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250818 control chromosomes. c.5557T>A has been reported in the literature as a VUS within the settings of multigene panel testing in a cohort of over 1000 Indian patients affected with Hereditary Breast and/or Ovarian Cancer (example, Singh_2018). This reports does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed repair (HDR) activity (example, Findlay_2018). Of note, other missense variants at the same codon, namely p.Tyr1853His and p.Tyr1853Asp were also reported to be loss of function in this study. Furthermore, at-least one additional variant located at the same codon, c.5558A>G (p.Tyr1853Cys) has been classified as pathogenic at our laboratory suggesting the relevance of this codon to overall functionality. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG PS3) as sufficient weightage for categorization as likely pathogenic (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 29470806, 32257056). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Until additional clinical reports further corroborating the directionality of evidence outlined above are identified, the variant was classified as likely pathogenic.
Brotman Baty Institute, University of Washington	RCV001072339	SCV001237701	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357015	SCV001552338	uncertain significance	not provided		no assertion criteria provided	clinical testing